Biology subjects

Alumkal, J. J.

Publications and source records attributed to Alumkal, J. J..

4 recordsLinked to original sources

bioRxiv2026

Global mRNA 3'UTR lengthening in small-cell neuroendocrine carcinoma

Small-cell neuroendocrine carcinoma (SCNC) is a rare but highly malignant tumor subtype that primarily arises in the lung, also rarely in other organs, and as a consequence of treatment induced lineage transdifferentiation of prostate adenocarcinomas. The molecular convergence of SCNC across diverse tissues enables its identification through conserved SCNC-specific molecular markers, facilitating tumor subtype classification. As a critical post-transcriptional regulatory mechanism, alternative polyadenylation (APA) modulates 3'UTR length and significantly impacts tumor progression. However, its role in SCNC remains largely unclear. Here, we report a global 3'UTR lengthening pattern driven by APA in SCNC. We identified a set of conserved 3'UTR lengthening events across SCNCs of different tissue origins, which are strongly associated with neural development and related signaling pathways. Furthermore, we developed a neural network-based prediction model to classify SCNC by leveraging these specific APA signatures. Our study provides new insights into the post-transcriptional landscape of SCNCs and highlights APA signatures as promising biomarkers for SCNC identification.

cancer biology↗

bioRxiv2025

Increasing Stemness Drives Prostate Cancer Progression, Plasticity, Therapy Resistance and Poor Patient Survival

BackgroundCancer progression is often accompanied by dedifferentiation and acquisition of stem cell-like properties (stemness). In prostate cancer (PCa), lineage plasticity and therapy resistance remain major clinical challenges, yet a unified quantitative transcriptomic framework connecting stemness, androgen receptor (AR) signaling, castration resistance, and disease progression across the PCa continuum is lacking. MethodsWe integrated 87,339 transcriptomic profiles from 33 preclinical and clinical datasets spanning the PCa continuum from normal prostate and treatment-naive primary PCa (Pri-PCa) to PCa treated with neoadjuvant ADT (nADT) and metastatic castration-resistant PCa (mCRPC), with single-cell RNA-seq analyses encompassing 115,197 cells. Cancer stemness was quantified using a transcriptome-derived mRNA-based Stemness Index (mRNAsi; hereafter Stemness), and a 12-gene PCa-Stem signature was developed to capture PCa-specific stemness. Stemness, PCa-Stem, canonical AR activity (c_AR-A), castration-reprogrammed AR activity (cr_AR-A), RB1-loss, PTEN-loss, and MYC activity signatures were quantified across cohorts. Functional validation included MYC inhibition and representative PCa-Stem signature gene depletion in PCa models. Clinical prognostic significance was evaluated in independent patient cohorts. ResultsThe Stemness score and c_AR-A increased concordantly during early prostate tumorigenesis but diverged with PCa progression: as Gleason grade increased, c_AR-A declined while Stemness continually increased. mCRPC exhibited the highest Stemness and lowest c_AR-A, a pattern recapitulated in Pten/Rb1/Trp53-deficient mouse models. Global Stemness increased progressively across the PCa continuum, was enriched in aggressive PAM50-LumB and PCS1 subtypes, associated with proliferative and lineage plasticity programs, and predicted poor patient survival. The newly derived 12-gene PCa-Stem signature provided a PCa-specific molecular representation of Stemness and tracked disease progression and poor patient survival. Network analyses identified a coordinated mitotic regulatory program linking MYC activity, RB1-loss, cr_AR-A, and the PCa-Stem signature. Spatial and single-cell transcriptomic analyses localized the PCa-Stem program to lineage plasticity-related epithelial cells and demonstrated progressive expansion of PCa-Stem epithelial cells during PCa progression. Functional perturbation of representative PCa-Stem signature genes, as well as genetic and pharmacological MYC inhibition, consistently suppressed Stemness-associated phenotypes in diverse PCa models. ConclusionsCancer Stemness quantitatively captures PCa aggressiveness, lineage plasticity, treatment resistance, disease progression, and poor patient survival. cr_AR-A, RB1 loss, and MYC activation cooperate to reinforce the high-Stemness state and therapy resistance in mCRPC. Collectively, our work establishes a trajectory-integrated transcriptomic framework defining cancer Stemness as a quantifiable molecular and clinical determinant of PCa aggressiveness, lineage plasticity, disease progression, therapy resistance and patient survival.

cancer biology↗

bioRxiv2024

Deciphering single-cell heterogeneity and cellular ecosystem dynamics during prostate cancer progression

Prostate cancer (PC) progresses from benign epithelium through pre-malignant lesions, localized tumors, metastatic dissemination, and castration-resistant stages, with some cases exhibiting phenotype plasticity under therapeutic pressure. However, high-resolution insights into how cell phenotypes evolve across successive stages of PC remain limited. Here, we present the Prostate Cancer Cell Atlas (PCCAT) by integrating [~]710,000 single cells from 197 human samples covering a spectrum of tumor stages. This comprehensive analysis dissects the cellular landscape and characterizes key cell types and molecular features that associate with PC progression and prognosis. In malignant cells, we highlight a distinctive profile denoted by high Major Histocompatibility Complex (MHC) expression, low Androgen Receptor (AR) activity, and enhanced stemness programs associated with enzalutamide resistance. Moreover, we reveal several cell states strongly correlated with PC progression and adverse prognosis, including lineage plasticity-like malignant cells (LPCs), neuroendocrine tumor cells, pericytes, and matrix cancer-associated fibroblasts (mCAFs). Furthermore, we uncover shared cell states that underpin the immune suppressive tumor microenvironment in advanced PC, including activated regulatory T cells, exhausted CD8+ T cells, and SPP1-expressing macrophages. Lastly, we pinpoint a spatial niche composed of mCAFs and SPP1-expressing macrophages localized near the tumor boundary in aggressive PC, which correlates with poor prognosis. Overall, our work provides a valuable resource and offers deeper insights into the diverse cell states, dynamics, and functional characteristics involved in PC progression at single-cell resolution.

cancer biology↗

bioRxiv2020

Autoantibody landscape of advanced prostate cancer

Although the importance of T-cell immune responses is well appreciated in cancer, autoantibody responses are less well-characterized. Nevertheless, autoantibody responses are of great interest, as they may be concordant with T-cell responses to cancer antigens or predictive of response to cancer immunotherapies. We performed serum epitope repertoire analysis (SERA) on a total of 1,229 serum samples obtained from a cohort of 72 men with metastatic castration-resistant prostate cancer (mCRPC) and 1,157 healthy control patients to characterize the autoantibody landscape of mCRPC. Using whole-genome sequencing results from paired solid-tumor metastasis biopsies and germline specimens, we identified tumor-specific epitopes in 29 mutant and 11 non-mutant proteins. Autoantibody enrichments for the top candidate autoantigen (NY-ESO-1) were validated using ELISA performed on the prostate cancer cohort and an independent cohort of 106 patients with melanoma. Our study recovers antigens of known importance and identifies novel tumor-specific epitopes of translational interest in advanced prostate cancer. Statement of significanceAutoantibodies have been shown to inform treatment response and candidate drug targets in various cancers. We present the first large-scale profiling of autoantibodies in advanced prostate cancer, utilizing a new next-generation sequencing-based approach to antibody profiling to reveal novel cancer-specific antigens and epitopes. Disclosure of Potential Conflicts of InterestJJA reports receiving consulting income from Janssen Biotech and Merck and honoraria from Astellas for speakers fees. MR reports receiving commercial research support from Novartis, Johnson & Johnson, Merck, Astellas, and Medivation, and is a consultant/advisory board member for Constellation Pharmaceuticals, Amgen, Ambrx, Johnson & Johnson, and Bayer. A.R. has received honoraria from consulting with Amgen, Bristol-Myers Squibb, Chugai, Dynavax, Genentech, Merck, Nektar, Novartis, Roche and Sanofi, is or has been a member of the scientific advisory board and holds stock in Advaxis, Arcus Biosciences, Bioncotech Therapeutics, Compugen, CytomX, Five Prime, RAPT, ImaginAb, Isoplexis, Kite-Gilead, Lutris Pharma, Merus, PACT Pharma, Rgenix and Tango Therapeutics. FYF serves on the advisory board for Dendreon, EMD Serono, Janssen Oncology, Ferring, Sanofi, Blue Earth Diagnostics, Celgene, consults for Bayer, Medivation/Astellas, Genetech, and Nutcracker Therapeutics, has honoraria from Clovis Oncology, and is a founder and has an ownership stake in PFS Genomics. SGZ and FYF have patent applications with Decipher Biosciences. SGZ and FYF have a patent application licensed to PFS Genomics. SGZ and FYF have patent applications with Celgene. WAH, RW, KK, PSD, and JCS have ownership of stocks or shares at Serimmune, paid employment at Serimmune, board membership at Serimmune, and patent applications on behalf of Serimmune.

cancer biology↗