Biology subjects

Link, J.

Publications and source records attributed to Link, J..

3 recordsLinked to original sources

bioRxiv2025

Long Noncoding RNAs Enforce Pancreatic Cancer Identity and Block Reprogramming

The Yamanaka factors (OCT4, SOX2, KLF4, and MYC; OSKM) can rejuvenate aging phenotypes in somatic cell types by resetting the epigenetic landscape. Curiously, most solid tumor cells remain largely resistant to reprogramming despite their well-documented plasticity, and the underlying mechanisms are unclear. Here, we combined genomic profiling and in vivo assays to investigate OSKM-mediated reprogramming of pancreatic ductal adenocarcinoma (PDAC). In the initial stages, we found that cancer-specific genes were refractory while mesodermal/ECM programs, normally silenced by PRC2, were aberrantly upregulated. A CRISPR interference screen for OSKM reprogramming coupled with functional analyses revealed that suppression of cancer-associated long noncoding RNAs (lncRNAs) erased malignant epithelial programs, restored tumor suppressor activity, and impaired tumorigenicity in vivo. We further identified that ATXN7L3-AS1 lncRNA sustains the PDAC malignant identity through its association with active epithelial oncogenic programs and poised PRC2-targeted developmental genes, thereby supporting both plasticity and memory. Thus, by exploring why cancer cells are resistant to reprogramming, we identify lncRNAs as gatekeepers of malignant identity, suggesting that targeting lncRNAs could be a generalizable therapeutic strategy in treating solid tumors.

cancer biology↗

bioRxiv2021

High-content single-cell combinatorial indexing

Single-cell genomics assays have emerged as a dominant platform for interrogating complex biological systems. Methods to capture various properties at the single-cell level typically suffer a tradeoff between cell count and information content, which is defined by the number of unique and usable reads acquired per cell. We and others have described workflows that utilize single-cell combinatorial indexing (sci)1, leveraging transposase-based library construction2 to assess a variety of genomic properties in high throughput; however, these techniques often produce sparse coverage for the property of interest. Here, we describe a novel adaptor-switching strategy, s3, capable of producing one-to-two order-of-magnitude improvements in usable reads obtained per cell for chromatin accessibility (s3-ATAC), whole genome sequencing (s3-WGS), and whole genome plus chromatin conformation (s3-GCC), while retaining the same high-throughput capabilities of predecessor sci technologies. We apply s3 to produce high-coverage single-cell ATAC-seq profiles of mouse brain and human cortex tissue; and whole genome and chromatin contact maps for two low-passage patient-derived cell lines from a primary pancreatic tumor.

genetics↗

bioRxiv2019

Acidic fibroblast growth factor underlies microenvironmental regulation of MYC in pancreatic cancer

Despite a critical role for MYC as an effector of oncogenic RAS, strategies to target MYC activity in RAS-driven cancers are lacking. Oncogenic KRAS is insufficient to drive tumorigenesis, while addition of modest overexpression of MYC drives robust tumor formation, suggesting that mechanisms beyond the RAS pathway play key roles in MYC regulation and RAS-driven tumorigenesis. Here we show that acidic fibroblast growth factor (FGF1) derived from cancer-associated fibroblasts (CAFs) cooperates with cancer cell-autonomous signals to increase MYC level, promoter occupancy, and activity. FGF1 is necessary and sufficient for paracrine regulation of MYC protein stability, signaling through AKT and GSK-3{beta}. These signals cooperate with, but are distinct from, cell-autonomous signals from oncogenic KRAS which stabilize MYC. Human pancreatic cancer specimens reveal a strong correlation between stromal CAF content and MYC protein level in the neoplastic compartment, and identify CAFs as the specific source of FGF1 in the tumor microenvironment. Together, our findings demonstrate that MYC is coordinately regulated by cell-autonomous and microenvironmental signals, and establish CAF-derived FGF1 as a novel paracrine regulator of oncogenic transcription.\n\nStatement of significanceOur work highlights an unanticipated role for the tumor microenvironment in the regulation of MYC protein stability in pancreatic cancer cells and identifies CAF-derived FGF1 as a novel, specific paracrine regulator of MYC.

cancer biology↗