Projects |

Biomarker Discovery

Thu, 26 Mar 2026 00:00:00 +0000

Rewiring Cancer Cells Through Ribosome Biogenesis and RNA Splicing

Our research explores the critical vulnerabilities of hard-to-treat cancers, focusing on the unexpected intersection of ribosome biogenesis and RNA splicing. In foundational work published in Cell Chemical Biology, we uncovered a novel tumor-suppressive response triggered by inhibiting RNA Polymerase 1 (Pol 1).

While ribosome biogenesis is a well-known hallmark of cancer, we discovered that the ribosomal protein RPL22 plays a dual role as a critical regulator of RNA splicing. By targeting Pol 1 with novel inhibitors like BOB-42, we can trigger a unique stress response that rewires how cancer cells splice RNA and produce proteins.

Clinical Translation and Future Directions

Our findings show that tumors with mutations in RPL22—or high levels of MDM4 and RPL22L1—are exceptionally sensitive to Pol 1 inhibition. These alterations are highly prevalent in mismatch repair-deficient (MMRd) cancers, such as colorectal, stomach, and uterine cancers, which are often resistant to existing therapies. In preclinical models, targeting this pathway reduced tumor growth by up to 77%. Moving forward, our laboratory is actively investigating how altering cancer cell RNA splicing might modulate tumor antigenicity, potentially paving the way for powerful new combinations with immunotherapies.

Drug Resistance

Thu, 26 Mar 2026 00:00:00 +0000

Targeting Ribosome Biogenesis in Cancer

Increased ribosome biogenesis is a fundamental hallmark of cancer. Targeting this hyperactive process with RNA polymerase I (Pol I) inhibitors—such as the first-in-class small molecule BMH-21—represents a highly promising therapeutic strategy across multiple tumor types. However, cancer cells often exhibit diverse and heterogeneous responses to these treatments, underscoring a critical need to understand the precise molecular mechanisms that drive drug resistance.

Uncovering Mechanisms of Therapeutic Resistance

To decode these cellular survival strategies, our laboratory utilizes genome-wide CRISPR-Cas9 positive selection screens to identify the master genetic regulators that modulate how cancer cells respond to Pol I inhibition. By interrogating human cancer models, we have successfully mapped high-confidence genetic pathways that dictate therapeutic sensitivity and resistance, operating independently of common tumor suppressors like p53.

The Role of Compensatory Translation

Through integrated approaches utilizing polysome profiling, Ribo-seq, and RNA-seq, we have discovered exactly how resistant cancer cells mount a defense against transcription stress. Under the severe ribosome biogenesis defect caused by Pol I inhibitors, these resilient cells evoke a compensatory, selective translation of specific ribosomal proteins. By elevating the translation efficiency of these key mRNAs, cancer cells can maintain enough translational capacity to bypass the Pol I inhibition and survive.

Future Directions

Our ongoing research focuses on how this maintenance of specific translational capacity directly fuels treatment resistance. By understanding the complex cellular workarounds that cancer cells use to survive severe biogenesis defects, we aim to uncover unforeseen vulnerabilities and establish the foundation for powerful, rationally designed drug combinations in the clinic.

Population Genetics

Thu, 26 Mar 2026 00:00:00 +0000

Research Foundation: Redefining Ribosomal RNA

The Dogma

Human ribosomal RNA (rRNA) genes are the fundamental building blocks of ribosomes—the essential microscopic machineries responsible for translating proteins. For decades, the foundational sequences of these genes were considered universally conserved, or “untouchable,” with the assumption that they were identical across all human populations.

The Discovery

Driven by the need to understand how rRNA synthesis is altered in cancer, we undertook a massive bioinformatics analysis using whole-genome sequencing data from the 1000 Genomes Project. Analyzing 2,504 individuals across 26 distinct global populations, we uncovered a surprising twist: human rRNA genes exhibit widespread, ancestry-dependent genetic variation.

Key Findings: We identified 3,791 variant positions on the rRNA gene, including 470 distinct variants specifically located on the 28S rRNA segment—a critical component of the protein-translating ribosome.

Evolutionary Significance: Many of these variants are strongly segregated by geographic population, suggesting they are ancient, ancestry-dependent traits that have been evolutionarily retained due to their functional importance.

The Future: Implications for Cancer Therapeutics This discovery shatters the assumption of universally conserved human rRNA and opens an entirely new frontier in molecular biology. Because highly variable sites exist in the exact locations previously expected to be unaltered, the way variant rRNAs are built into ribosomes could significantly impact how those ribosomes function.

Building on this, our laboratory seeks to functionally assess how these 28S rRNA variants drive cancer development and therapeutic resistance. By understanding these diverse mechanisms, we aim to pave the way for highly targeted treatments, including the continued development and refinement of novel RNA Polymerase I inhibitors.