Targeting the bicarbonate transporter SLC4A4 overcomes immunosuppression and immunotherapy resistance in pancreatic cancer

Cappellesso, Federica; Orban, Marie-Pauline; Shirgaonkar, Niranjan; Berardi, Emanuele; Serneels, Jens; Neveu, Marie‐Aline; Molfetta, Daria Di; Piccapane, Francesca; Caroppo, Rosa; Debellis, Lucantonio; Ostyn, Tessa; Joudiou, Nicolas; Mignion, Lionel; Richiardone, Elena; Jordan, Bénédicte F.; Gallez, Bernard; Corbet, Cyril; Roskams, Tania; DasGupta, Ramanuj; Tejpar, Sabine; Matteo, Mario Di; Taverna, Daniela; Reshkin, Stephan J.; Topal, Baki; Virga, Federico; Mazzone, Massimiliano

doi:10.1038/s43018-022-00470-2

Cited by 63 publications

(39 citation statements)

References 66 publications

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“…Mazzone and colleagues have demonstrated that PDAC cells express SLC4A4 a transporter that actively imports bicarbonate. 91 The accumulation of bicarbonate in PDAC cells increases intracellular pH, which in turn buffers against the accumulation of H + ions that are generated by glycolysis. This buffering allows glycolysis to proceed at a faster rate generating increased levels of H + /lactate, which PDAC cells readily export into the interstitial space.…”

Section: Mechanistic Insights Into Therapy Responsementioning

confidence: 99%

Refining the Treatment of Pancreatic Cancer From Big Data to Improved Individual Survival

Bailey

Zhou

et al. 2023

Function

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Pancreatic cancer is one of the most lethal cancers world-wide most notably in Europe and North America. Great strides have been made in combining the most effective conventional therapies to improve survival at least in the short and medium term. The start of treatment can only be made once a diagnosis is made, which at this point the tumor volume is already very high in the primary cancer and systemically. If caught at the earliest opportunity (in circa 20% patients) surgical resection of the primary followed by combination chemotherapy can achieve 5-year overall survival rates of 30–50%. A delay in detection of even a few months after symptom onset will result in the tumor having only borderline resectabilty (in 20–30% of patients), in which case the best survival is achieved by using short course chemotherapy before tumor resection as well as adjuvant chemotherapy. Once metastases become visible (in 40–60% of patients) cure is not possible, palliative cytotoxics only being able to prolong life by few months. Even in apparently successful therapy in resected and borderline resectable patients the recurrence rate is very high. Considerable efforts to understand the nature of pancreatic cancer through large scale genomics, transcriptomics and digital profiling, combined with functional preclinical models, using genetically engineered mouse models and patient derived organoids, have identified the critical role of the tumor microenvironment in determining the nature of chemo- and immuno-resistance. This functional understanding has powered fresh and exciting approaches for the treatment of this cancer.

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Section: Mechanistic Insights Into Therapy Responsementioning

confidence: 99%

Refining the Treatment of Pancreatic Cancer From Big Data to Improved Individual Survival

Bailey

Zhou

et al. 2023

Function

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“…NBC transporters are able to load or extrude protons from the cell via sodium-bicarbonate transport. NBCe1, a type of NCB transporter, is present in pancreatic cancer cells and functions as an acid extruder that supports tumoral growth and metastasis ( Cappellesso et al, 2022 ). iii) Monocarboxylate transporters (MCT).…”

Section: Hv1 Channel In Cancer Biology: Ph Control As One Of the Gove...mentioning

confidence: 99%

Role of voltage-gated proton channel (Hv1) in cancer biology

et al. 2023

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The acid-base characteristics of tumor cells and the other elements that compose the tumor microenvironment have been topics of scientific interest in oncological research. There is much evidence confirming that pH conditions are maintained by changes in the patterns of expression of certain proton transporters. In the past decade, the voltage-gated proton channel (Hv1) has been added to this list and is increasingly being recognized as a target with onco-therapeutic potential. The Hv1 channel is key to proton extrusion for maintaining a balanced cytosolic pH. This protein-channel is expressed in a myriad of tissues and cell lineages whose functions vary from producing bioluminescence in dinoflagellates to alkalizing spermatozoa cytoplasm for reproduction, and regulating the respiratory burst for immune system response. It is no wonder that in acidic environments such as the tumor microenvironment, an exacerbated expression and function of this channel has been reported. Indeed, multiple studies have revealed a strong relationship between pH balance, cancer development, and the overexpression of the Hv1 channel, being proposed as a marker for malignancy in cancer. In this review, we present data that supports the idea that the Hv1 channel plays a significant role in cancer by maintaining pH conditions that favor the development of malignancy features in solid tumor models. With the antecedents presented in this bibliographic report, we want to strengthen the idea that the Hv1 proton channel is an excellent therapeutic strategy to counter the development of solid tumors.

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“…At the same time, these therapeutic efforts aim to reverse the secondary tumoral environmental-extracellular acidification (TME) characteristic of the CPR of malignant cells and tissues. CPR is also a fundamental factor in the escape of malignant tumors from the organism's immune defense mechanisms [66,67].…”

Section: Therapeutic Implications: Closing Gapsmentioning

confidence: 99%

The Prime and Integral Cause of Cancer in the Post-Warburg Era

Harguindey¹,

Reshkin

Alfarouk³

2023

Cancers

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Back to beginnings. A century ago, Otto Warburg published that aerobic glycolysis and the respiratory impairment of cells were the prime cause of cancer, a phenomenon that since then has been known as “the Warburg effect”. In his early studies, Warburg looked at the effects of hydrogen ions (H+), on glycolysis in anaerobic conditions, as well as of bicarbonate and glucose. He found that gassing with CO2 led to the acidification of the solutions, resulting in decreased rates of glycolysis. It appears that Warburg first interpreted the role of pH on glycolysis as a secondary phenomenon, a side effect that was there just to compensate for the effect of bicarbonate. However, later on, while talking about glycolysis in a seminar at the Rockefeller Foundation, he said: “Special attention should be drawn to the remarkable influence of the bicarbonate…”. Departing from the very beginnings of this metabolic cancer research in the 1920s, our perspective advances an analytic as well as the synthetic approach to the new “pH-related paradigm of cancer”, while at the same time addressing the most fundamental and recent changing concepts in cancer metabolic etiology and its potential therapeutic implications.

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Targeting the bicarbonate transporter SLC4A4 overcomes immunosuppression and immunotherapy resistance in pancreatic cancer

Cited by 63 publications

References 66 publications

Refining the Treatment of Pancreatic Cancer From Big Data to Improved Individual Survival

Refining the Treatment of Pancreatic Cancer From Big Data to Improved Individual Survival

Role of voltage-gated proton channel (Hv1) in cancer biology

The Prime and Integral Cause of Cancer in the Post-Warburg Era

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