Breakthrough Discovery from UTokyo's RCAST Sheds Light on Cancer Cell Adaptation

Researchers at the University of Tokyo have made a significant advance in understanding how cancer cells thrive in the harsh conditions of tumors. Led by Associate Professor Tsuyoshi Osawa from the Research Center for Advanced Science and Technology (RCAST), the team explored how cancer cells endure the acidic tumor microenvironment, a common feature in solid tumors like pancreatic cancer. This environment, characterized by low pH levels due to excessive glycolysis, typically challenges cell survival, yet cancer cells not only persist but gain aggressive traits.

The study reveals that moderate acidity around pH 6.8 triggers adaptations allowing cells to detach from surfaces, survive in suspension, and initiate new tumors more effectively. This plasticity could explain why tumors resist treatments and metastasize. For Japanese higher education, this underscores UTokyo's leadership in interdisciplinary cancer research, blending nutriomics, oncology, and bioengineering.

Understanding the Acidic Tumor Microenvironment

The tumor microenvironment (TME) refers to the complex ecosystem surrounding cancer cells, including immune cells, blood vessels, and extracellular matrix. In solid tumors, rapid cell proliferation leads to the Warburg effect, where cells favor glycolysis even with oxygen present, producing lactic acid and protons that lower extracellular pH to 6.5-6.8, sometimes dipping to 5.6.

In Japan, where cancer is the leading cause of death with over 380,000 new cases annually and pancreatic cancer showing a dismal five-year survival rate below 10%, targeting this acidity holds promise. UTokyo's findings highlight how pH gradients drive tumor evolution, informing strategies at institutions like the National Cancer Center Research Institute.

Step-by-step, cancer cells export protons via transporters like MCT1 and NHE1, acidifying the TME. This suppresses immune responses and normal cell function while selecting resilient cancer clones. UTokyo researchers cultured pancreatic cancer lines like PANC1 and MIA PaCa-2 at varying pH to mimic this.

UTokyo Team's Experimental Approach

At RCAST's Division of Nutriomics and Oncology, Osawa's lab specializes in how nutrients and extreme TME conditions like acidity shape cancer metabolism. Using live-cell imaging with calcein-AM dye, they observed membrane integrity at different pH levels. At pH 5.6, cells underwent necroptosis—a programmed necrosis involving MLKL phosphorylation—inhibited by Nec-1.

RNA sequencing of floating cells at pH 6.8 showed upregulated respiratory chain genes (e.g., DHRS2, PGAM2) and complement pathway (C3, C5). A genome-wide CRISPR-Cas9 screen pinpointed FAM129C as essential for acid tolerance; its knockout slashed viability.

Key Mechanisms: FAM129C-PIGR Axis

FAM129C emerges as a pH sensor suppressing PIGR (polymeric immunoglobulin receptor), modulating complement activation and macrophage infiltration. In mouse xenografts, FAM129C overexpression curbed tumor growth by elevating PIGR, reducing protumor immunity. Conversely, PIGR-high tumors resisted anti-PD-L1 but succumbed to combined complement inhibitor (PMX-53) and immunotherapy.

This axis explains immune evasion in acidic niches. Pancreatic tumors, prevalent in Japan with rising incidence, exemplify this; UTokyo's data links low FAM129C to poor prognosis across cancers.

Photo by Karl Solano on Unsplash

• FAM129C knockout boosts proliferation at pH 6.8 via unchecked complement.
• PIGR overexpression recruits M2 macrophages, fostering growth.
• Therapy combo shrinks tumors by boosting CD8 T-cells and IFN-γ.

Osawa Lab's Nutriomics Focus at RCAST

RCAST, UTokyo's hub for advanced tech, fosters labs like Osawa's, integrating omics data with nutrition to tackle TME extremes. Previous works decoded hypoxia and starvation adaptations, building to this acid study. Osawa, trained in chemistry and oncology, leads efforts yielding high-impact papers.

Collaborators span Chiba University, Hokkaido University, and international sites, reflecting UTokyo's global reach. For students, RCAST offers PhD programs blending engineering and medicine, with JSPS grants fueling such innovation.

Japan's Investment in Cancer Research

Japan allocates ~€1.6 billion yearly to cancer research, 3.6% of global spend, via AMED and MEXT. UTokyo receives substantial funding, topping oncology rankings. This study, likely JSPS-backed, aligns with the Basic Cancer Plan targeting immunotherapy and microenvironment therapies.

In 2026, pancreatic cancer claims ~35,000 lives in Japan; acidic TME research could boost survival via pH-targeted drugs. Universities like Kyoto and Osaka contribute, but UTokyo leads with 20% of top papers.

Implications for Cancer Therapy Development

The FAM129C pathway offers druggable targets. Complement inhibitors like PMX-53, already trialed, synergize with checkpoint blockers. pH-modulating agents could prevent plasticity.Read the full Cell Reports study for protocols.

In Japan, clinical translation via NCCH trials could fast-track. UTokyo's preclinical models predict human responses, aiding pharma like Takeda.

Role in Japanese Higher Education and Training

UTokyo trains ~3,000 grad students yearly in life sciences; RCAST's programs attract top talent via MEXT scholarships. This discovery inspires curricula in tumor biology, drawing international postdocs. Japan's unis host 10% global cancer researchers, fostering collaborations.

Career paths abound: faculty positions, biotech startups via UTokyo Innovation Platform.

Photo by Karl Solano on Unsplash

Future Outlook and Ongoing Research

Osawa Lab eyes multi-omics for TME mapping; upcoming trials test pH sensors. Nationally, Cancer Moonshot aims ¥100B funding by 2030. UTokyo's edge positions it centrally.

Challenges: translating to clinics amid aging population (30% over 65 by 2030). Solutions: AI integration for screens, as in CRISPR data.

Stakeholder Perspectives in Japan's Academia

Experts praise the work: "Reveals TME's dual role in death vs. plasticity," notes a Chiba prof. Students benefit from hands-on CRISPR training. Industry partners eye licensing.

Broader: boosts Japan's QS oncology ranking, attracts funding.