Tolerance to extracellular acidic pH facilitates tumor plasticity

Area of Science:

• Biochemistry
• Cell Biology
• Oncology

Background:

• Cancer cells exhibit altered metabolism, leading to acidic tumor microenvironments.
• The mechanisms by which cancer cells survive and adapt to acid stress are not fully understood.

Purpose of the Study:

• To investigate cancer cell survival mechanisms under acidic conditions.
• To identify molecular players regulating acid tolerance and tumor initiation.
• To explore therapeutic strategies targeting pH-dependent cancer cell death.

Main Methods:

• Cancer cell culture under varying pH conditions.
• RNA sequencing to analyze gene expression changes.
• Genome-wide CRISPR-Cas9 knockout screening.
• In vivo xenograft studies and drug treatment.

Main Results:

• Moderate acidity (pH 6.8) promotes anchorage-independent survival and tumor initiation, while severe acidity (pH 5.6) induces necroptosis.
• Acidic conditions activate respiratory chain and complement pathways, facilitating cancer cell adaptation.
• FAM129C was identified as a key regulator of acid tolerance, influencing PIGR expression.
• Combined anti-PD-L1 and complement inhibition showed synergistic anti-tumor effects in PIGR-overexpressing tumors.

Conclusions:

• Acidic stress triggers pathways enabling cancer cells to evade necroptosis and enhance tumor plasticity.
• The FAM129C-PIGR axis plays a role in tumor growth and immune evasion.
• Targeting pH-dependent cell death pathways presents a promising therapeutic avenue for cancer treatment.