- by Lin, J., Xun, Z., Qian, F., Chen, Z., Hu, W., Liu, W., Wu, Y., Yuan, H., Yin, L., Wang, Y., Huang, X., Dang, Y., Xiao, B., Wu, J., Gao, W., Wei, J., Li, Q., Tu, M., Zhou, J., Feng, X., Lu, Z., Wen, L., Jiang, K., Liang, H.Pancreatic ductal adenocarcinoma (PDAC) frequently recurs after surgical resection, indicating that residual disease is sustained by coordinated tumor-microenvironment interactions. To define the biological basis of recurrence, we leverage large-scale clinical data from 2,710 patients, deeply characterized multi-omics profiling (whole-exome, bulk RNA, and single-nucleus sequencing) of 36 matched primary and locally recurrent PDACs, an in-house multiplex spatial imaging cohort of 190 patients, and extensive public datasets. Recurrent tumors were characterized by increased KRAS mutant allele dosage and reinforced KRAS signaling, accompanied […]
- by Vanmechelen, M., Nazari, P., Beckervordersandforth, J. J. C., Caprioli, C., Leunissen, D. D. J. G., Cole, B., Bravo Gonzalez-Blas, C., Decraene, B., De Visser, Y., Shankar, G., Verduin, M., Pantano, D., Bevers, S., Moors, T., Zielinski, S., Telang, J., Messiaen, J., Van Herck, Y., Geens, E., Eekers, D., Claeys, A., Derweduwe, M., zur Hausen, A. A., Chui, J., Bosisio, F. M., Weyns, F., Daenekindt, T., Oosterbos, C., Van Eyken, P., Govers, M., Mennens, F., Hovinga, K. K. E., De Vleeschouwer, S., Clement, P., Broen, M. M. P. G., Vooijs, M., Sciot, R., Antoranz Martinez, A., Pey, J., Speel, E. J.Glioblastoma remains an invariably recurring and lethal brain tumor shaped by complex interactions between malignant and microenvironmental cells. How these interactions evolve under first-line standard-of-care (SOC) therapy remains unclear. We performed spatial single-cell profiling of 671 paired newly diagnosed and recurrent glioblastoma samples from 96 patients to map tumor-ecosystem evolution and its clinical relevance. We delineated five distinct patient subgroups, each characterized by unique ecosystem trajectories that correlated with clinical outcome. Patients whose tumors transitioned into oligodendrocyte-progenitor-like niches with enhanced […]
- by Gu, Y., Ruan, L., Hou, Y., Gilbert-Ross, M., Brown, T., Kalinsky, K. M., Badve, S. S., Gokmen-Polar, Y.Resistance to cyclin-dependent kinase 4/6 inhibitors remains a major clinical challenge in treating estrogen receptor-positive breast cancer, with no reliable predictive biomarkers currently available for patient selection. To investigate resistance mechanisms, we generated drug-tolerant persisters (DTPs) to abemaciclib and palbociclib in a panel of estrogen receptor-positive breast cancer cell lines. Functional analyses revealed that DTPs showed resistance to CDK4/6 inhibition, maintained G1 arrest, and exhibited increased senescence phenotype. To identify clinically relevant markers of resistance, we compared transcriptomic profiles from […]
- by Ferreiro-Miguens, R., Diez-Grandio, I., Soto-Feijoo, R., Ferreiro, L., Garcia, J., Otero-Alen, M., Abdulkader, I., Bernandez, B., Dominguez, E., Abal, M., Leon-Mateos, L.Thoracic malignancies, including lung adenocarcinoma (ADC) and malignant pleural mesothelioma (MPM), remain associated with poor prognosis and limited durable therapeutic responses in advanced stages. Although targeted therapies and immunotherapy have improved outcomes in selected patients, systemic chemotherapy continues to play a central role in routine clinical practice. However, treatment response is highly heterogeneous, and reliable predictive biomarkers of chemotherapy sensitivity are lacking. Both ADC and MPM frequently involve the pleural cavity and are commonly associated with malignant pleural effusion (MPE), […]
- by Rachman, T., Laframboise, W., Gallo, P., Petrosko, P., Liu, D., Kumar, R., Balic, M., Oesterreich, S., Foldi, J., Lee, A., Wagner, P., Bartlett, D., Schwartz, R., Carja, O.Liquid biopsy studies consistently report both elevated circulating cell-free DNA (cfDNA) concentrations and shortened fragment lengths in cancer. These features are often attributed to tumor-specific processes, despite tumor-derived cfDNA frequently constituting less than 1% of the total. Here, we consider an alternative explanation: Saturation of cfDNA clearance, which prolongs cfDNA circulation time, increases exposure to plasma nucleases and is expected to produce similar fragmentomic signatures independent of tumor burden. By combining a mechanistic model of cfDNA fragmentation with analyses of […]
- by Goldstein, M. E., Chu, B., Carillo, K. J., Orban, J., Toth, E. A., Fuerst, T. R.Controlling aberrant RAS signaling has been the subject of intensive efforts aimed at developing specific RAS inhibitors, small molecules that promote RAS degradation, and monobodies that inhibit RAS activity. Direct proteolytic degradation of RAS by site-specific proteases has received considerably less attention. A naturally-occurring protease from Vibrio vulnificus toxin cleaves all RAS isoforms at switch I and attenuates RAS signaling in cell models and patient-derived xenografts, thus demonstrating the potential of this approach. We previously designed a RAS-specific protease, called […]
- by Gall Mas, L., Kleinmanns, K., Pirttikoski, A., Santarelli, M., Stangeland, G., Dai, J., Marin Falco, M., Fontaneda-Arenas, D., Doerr, C., Hautaniemi, S., Hynninen, J., McCormac, E., Wennerberg, K., Bjorge, L., Vähärautio, A., Schwikowski, B.In high-grade serous carcinoma (HGSC), extensive intra-tumoral heterogeneity hinders complete eradication and remains a major obstacle to developing combination therapies capable of eliminating subpopulations resistant to standard-of-care treatment. Using single-cell RNA sequencing of 72 samples from 54 HGSC patients spanning treatment-naive, post-neoadjuvant chemotherapy and relapse stages, we established a carboplatin-anchored framework that identifies transcriptional signatures of intrinsic (pre-existing) and adaptive (therapy-induced) resistance in individual tumors and prioritizes mechanistically matched drugs to potentiate carboplatin efficacy. Candidate compounds were ranked by integrating […]
- by Stewart, E., Knupke, M., Collins, A., Chan, L. N.B-cell acute lymphoblastic leukemia (B-ALL) arises from lymphoid precursors that fail to complete normal B-cell maturation and frequently harbor activating mutations in the RAS-ERK pathway that promote leukemic survival and therapeutic resistance. During normal B-cell development, early precursors signal through the precursor B-cell receptor (pre-BCR), which supports survival and proliferation before transitioning to expression of the mature B-cell receptor (BCR). In B-ALL, leukemic blasts are typically arrested prior to BCR expression. Our prior work demonstrated that oncogenic RAS signaling functionally […]
- by Forjaz, A., Mojdeganlou, H., Valentin, A., Wetzel, M., Lvovs, D., Deshpande, A., Shin, S. M., Piya, S., Rajapakshe, K. I., Guerrero, P. A., Pedro, B. A., Sidiropoulos, D. N., Wu, P.-H., Bernard Pagan, V., Demystifying Pancreatic Cancer Therapies TeamLab,, Wirtz, D., Fertig, E. J., Kagohara, L. T., Ho, W. J., Kiemen, A. L., Wood, L. D.Resistance to systemic therapy is a major unmet challenge in pancreatic cancer. To identify potential mechanisms of resistance, we developed a novel 3D pipeline in clinical samples that uses deep learning to classify sensitive and persistent tumor cell populations based on morphological features, enabling subsequent molecular characterization of intratumoral heterogeneity. We applied this automated 3D pipeline to a cohort of human pancreatic cancer samples treated with neoadjuvant chemotherapy, identifying heterogeneity in response to therapy both between and within tumors. Application […]
- by Rojo, C., Vila, J. J., Guembe, L., Arrubla-Gamboa, A., Jusue-Irurita, V., Carrascosa-Gil, J., Rullan, M., Randez, J., Fernandez-Barrena, M. G., Huch, M., Urman, J., Avila, M. A., Berasain, C., Arechederra, M.Bile represents a clinically accessible biological fluid that can mitigates major limitations associated with tissue-based sampling for the generation of organoid models to study hepatobiliary disease, including biliary tract cancers where tissue availability is often limited. Importantly, bile can also enable the generation of non-malignant cholangiocyte organoids that are otherwise difficult to obtain. Here, we describe an operator-oriented, step-by-step protocol to generate organoids from fresh bile collected during endoscopic retrograde cholangiopancreatography (ERCP), together with two complementary workflows for siRNA delivery […]
- by Sfanos, K., Morton, R., Flores, J., Sosa, R., Ernst, S., Mummert, L., Hicks, J., Lotan, T. L., Lu, J., Jing, Y., Joshu, C., De Marzo, A. M.Background: Homozygous biallelic inactivation of CDKN1B is thought to be rare in cancer. Herein we evaluate the prevalence of intratumoral (subclonal) complete p27 protein loss (IPPL) in primary prostate cancer. Experimental Design: We used immunohistochemistry (IHC) for p27 in a large cohort of whole tissue sections from radical prostatectomy (n=412) and metastases from self-identified African American (AA) and European American (EA) individuals. IPPL was evaluated alongside CDKN1B mRNA in-situ hybridization and next generation sequencing of laser captured cancer regions. Cox […]
- by Morrow, S. K., Berryhill, C. A., White, E. E., Beach, C. J., Dixon, S. A. H., Zhang, E. Y., Davis, C., Mannion, E. M., Hickey, B. E., Mang, H. E., Ciesielski, M. D., Gampala, S., Saadatzadeh, M. R., Gyabaah, E. A., Collier, C. D., Cohen-Gadol, A., Pratilas, C. A., Pollok, K. E., Fishel, M., Clapp, D. W., Mitchell, D. K., Rhodes, S. D., Angus, S. P.Malignant peripheral nerve sheath tumors (MPNST) are aggressive sarcomas with limited systemic therapies and represent the leading cause of mortality for individuals with neurofibromatosis type 1 (NF1). Malignant progression can reactivate developmental precursor programs that are largely absent from normal nerve and benign tumors, creating tumor-selective vulnerabilities. Zinc finger protein 423 (ZNF423; also known as OAZ/ROAZ) is a developmentally regulated transcription factor that delays olfactory precursor differentiation and has been implicated in B cell malignancy. Here, we asked whether ZNF423 […]
- by Imbach, K. J., Cervilla, S., Grases, D., Bystrup, S., Fortian, A., Bernat-Peguera, A., Sibai, M., Valdivieso, L., Carballos, E., Guillen Sentis, P., Romeo, M., Porta-Pardo, E., Barretina, J.Acquired resistance to poly(ADP-ribose) polymerase inhibitors (PARPi) remains a major barrier to durable clinical benefit in patients with high-grade serous ovarian cancer (HGSOC), yet the profiles of tumors at resistance remain poorly understood. We profiled longitudinal HGSOC patient tumors spanning diagnosis, post-neoadjuvant therapy, and progression on PARPi with complementary spatial transcriptomics platforms, integrating single-cell resolution Xenium analysis in paired longitudinal cases with cohort-level Visium profiling. PARPi failure was associated with spatial remodeling of the tumor microenvironment, marked by hypoxia-associated malignant […]
- by Goossens, C., Lolos, C., Lopez-Perez, A., Kessels, M., Deom, E., Bletard, N., Bernard, P., Flasse, L., Voz, M. L.Pancreatic ductal adenocarcinoma (PDAC) is the most common form of pancreatic cancer and carries the poorest prognosis among all cancers, largely because it is frequently diagnosed at metastatic stages. It is therefore critical to identify reliable markers of preinvasive stages and to decipher the network driving preinvasive lesions to invasive carcinoma. Here, we generated a zebrafish model in which KRASG12D is specifically expressed in pancreatic acinar cells, inducing acinar-to-ductal metaplasia that faithfully mirrors mammalian tumorigenesis. Single cell RNA-seq allowed us […]
- by Stephanou, A., Shui, B., Mische, D., Byron, M., Katt, W. P., Chan, M., Grenier, J. K., De Vlaminck, I., Duhamel, G. E., Gujral, T. S., Sethupathy, P., Peralta, S.Canine acanthomatous ameloblastoma (CAA) is a locally invasive benign oral neoplasm that is difficult to distinguish from canine oral squamous cell carcinoma (COSCC) due to overlapping clinical, radiologic, and histologic features. Although both tumors exhibit MAPK pathway activation, their mutational landscapes are distinct. Furthermore, previous studies using bulk RNA sequencing (RNA-seq) have demonstrated pronounced differences in programs related to, among others, hypoxia, PI3K-AKT signaling, and cell proliferation. However, these bulk studies lacked the resolution to elucidate the cellular heterogeneity of […]
- by Belluti, S., Mularoni, V., Iseppato, N., Campani, V., Ronzio, M., Righi, V., Cuoghi, L., Rinaldi, A., Martinelli, T., Cani, O., Salsi, V., Alessandrini, A., Miserocchi, G., Dolfini, D., Zappavigna, V., Imbriano, C.Metabolic reprogramming is a fundamental strategy that allows colorectal cancer (CRC) cells to endure microenvironmental constraints and sustain malignant progression. Here, we identify the transcription factor NF-Y as a master regulator of glutamine metabolism in CRC, with particular relevance to the aggressive CMS4 subtype. Loss of function experiments, integrated with metabolomic and transcriptomic analyses, reveal a critical role for NF-YA in regulating glutamine metabolism in CRC cells. Complementary gain of function studies pinpoint NF-YAl as the isoform specifically driving glutamine-centered […]
- by Bennett, D., Wierdl, M., Chakraborty, S., Johnson, J. D., Akingbehin, V., Estevez-Prado, D., Feng, Y., Morsby, J. J., Harper, J., Mohammad, M. N. A., Pan, M., Ocasio-Martinez, N., Catlett, J. L., Nations, T. B., Dharia, N. V., Robichaud, A., Herman, A., Zhang, S., Kelly, J., Steele, J., Rusch, M., Wienand, K., Campbell, C. D., Alexe, G., Vazquez, F., Getz, G., Roberts, C. W., Mullighan, C. G., Sweet-Cordero, E. A., Reynolds, C. P., Koneru, B., Shelat, A. A., Durbin, A. D., Bernstein, E., Ma, X., Stegmaier, K., Geeleher, P., Guenther, L. M.Alternative lengthening of telomeres (ALT) is a telomerase-independent pathway used by aggressive cancers to maintain their replicative immortality. Because ALT is absent from normal human cells, it is an appealing target for cancer therapy, but the lack of ability to determine ALT status at scale has hindered target discovery. Here, we developed ALTitude, a tabular foundation model-based method that infers ALT from cell line whole-genome sequencing data, without need for paired germline sequences. We deployed ALTitude across the Cancer Dependency […]
- by Shiokawa, D., Sakai, H., Kanda, Y., Ohata, H., Asada, Y., Ochiai, H., Fukagawa, T., Sekine, S., Yatabe, Y., Morikawa, M., Nakagama, H., Okamoto, K.Metastasis remains the leading cause of cancer mortality, yet effective strategies to eliminate metastasis-initiating cells are lacking. Here, we dissected intratumoral heterogeneity in colon cancer using single-cell analyses and identified a KRT17+ slow-cycling cancer cell population that exhibits features of metastasis-initiating cells (L1CAM) and senescent-like cells (CDKN2A, BCL2L1). Spatial transcriptomics and immunostaining revealed that these cells localize at tumor-stroma interfaces, where they are closely associated with TGF-{beta}1-producing subset of cancer-associated fibroblasts (CAFs) and exhibit SMAD3 activation. Mechanistically, TGF-{beta}1 induces KRT17 […]
- by Wang, L., Pandit, A., Alam, S. K., Skauge, R., Gradilone, S. A., Hoeppner, L. H.Patients with advanced non-small cell lung cancer (NSCLC) and mutations in epidermal growth factor receptor (EGFR) benefit from EGFR tyrosine kinase inhibitors (TKIs). Osimertinib, a third-generation EGFR TKI, is standard first-line therapy for EGFR-mutated NSCLC, but most patients develop resistance to it. Here, we demonstrate that increased formation of primary cilia, microtubule-based sensory organelles, is associated with osimertinib-refractory NSCLC progression. EGFR-mutated, osimertinib-resistant human NSCLC cells had increased cilia formation and acetylation of -tubulin and reduced histone deacetylase 6 (HDAC6) activity […]
- by Swenson, S. A., Winship, C. B., Dobish, K. K., Wittorf, K. J., Law, H. C., Vose, J. M., Greiner, T., Green, M. R., Woods, N. T. R., Buckley, S. M.Mantle cell lymphoma (MCL) is one of the deadliest forms of Non-Hodgkins B-cell lymphoma. Typically, patients present with both overexpression of CyclinD1 and secondary mutations identified by genomic sequencing. Although MCL patients may initially respond to treatment, they eventually relapse and succumb to disease, highlighting the essential need to identify new targets for treatment. Here we performed proteomic profiling of healthy B cells and three different forms of B-cell malignancies, including MCL, to define the proteomic signature of MCL. We […]
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