Deciphering the role of endolysosomal Ca2+ signalling via two-pore channel 2 (TPC2) in cancer: from bench to bedside
Cancer is a major public health problem and one of the leading causes of death worldwide, necessitating the development of innovative cancer biomarkers/targets to improve detection, diagnosis, prognosis, and therapy. Cancer biomarkers have evolved into clinical tools that can improve the efficiency...
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| Other Authors: | |
| Format: | Thesis |
| Language: | English |
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2023
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| _version_ | 1797109166316191744 |
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| author | Alharbi, A |
| author2 | Parrington, J |
| author_facet | Parrington, J Alharbi, A |
| author_sort | Alharbi, A |
| collection | OXFORD |
| description | Cancer is a major public health problem and one of the leading causes of death worldwide, necessitating the development of innovative cancer biomarkers/targets to improve detection, diagnosis, prognosis, and therapy. Cancer biomarkers have evolved into clinical tools that can improve the efficiency of detection and guide the treatment of cancer patients by providing personalised therapy and information about expected cancer outcomes. There is increasing evidence that links two-pore channel 2 (TPC2, also known as TPCN2) to cancer, revealing the potential applications of TPC2 as a biomarker/ therapeutic target. My thesis studies have underscored the significant role of TPC2 in cancer immunology, biology, and genetics. Monocytes and macrophages are myeloid cells that play a vital role in inflammation, immunity, and cancer. The spleen is an important source of monocytes, which act as direct precursors of haematopoietic stem cell–derived macrophages. Proteins related to the physiological processes involved in the immune system and cancer were significantly altered in TPC1 knockout (KO), TPC2 KO, and TPC1/2 double KO mouse splenocytes, compared to WT controls, suggesting that TPCs may play significant roles in regulating innate immune system functions in various pathophysiological processes. My thesis studies have identified TPC2 as a major regulator of monocyte differentiation and macrophage development. In addition, my studies have revealed, for the first time, an important link between TPC2 and the release of two mediators that are opposed in their functions: IL-8 pro-inflammatory cytokine and IL-10 anti-inflammatory cytokine. Finally, I have discovered variants in the TPCN2 gene that are associated with cancer at the global level or 13 various cancer types at the local level, in the definition of tumour types, susceptibility, and prognosis in the UK-biobank. My thesis gives insights into the pathophysiological significance of TPC2 in cancer immunity and may contribute to the development of new genomics-based guidelines for cancer diagnosis and therapy. |
| first_indexed | 2024-03-07T07:36:33Z |
| format | Thesis |
| id | oxford-uuid:7ea5699b-e4dc-4622-9145-c87404cc06a0 |
| institution | University of Oxford |
| language | English |
| last_indexed | 2024-03-07T07:36:33Z |
| publishDate | 2023 |
| record_format | dspace |
| spelling | oxford-uuid:7ea5699b-e4dc-4622-9145-c87404cc06a02023-03-17T09:45:31ZDeciphering the role of endolysosomal Ca2+ signalling via two-pore channel 2 (TPC2) in cancer: from bench to bedside Thesishttp://purl.org/coar/resource_type/c_db06uuid:7ea5699b-e4dc-4622-9145-c87404cc06a0EnglishHyrax Deposit2023Alharbi, AParrington, JCancer is a major public health problem and one of the leading causes of death worldwide, necessitating the development of innovative cancer biomarkers/targets to improve detection, diagnosis, prognosis, and therapy. Cancer biomarkers have evolved into clinical tools that can improve the efficiency of detection and guide the treatment of cancer patients by providing personalised therapy and information about expected cancer outcomes. There is increasing evidence that links two-pore channel 2 (TPC2, also known as TPCN2) to cancer, revealing the potential applications of TPC2 as a biomarker/ therapeutic target. My thesis studies have underscored the significant role of TPC2 in cancer immunology, biology, and genetics. Monocytes and macrophages are myeloid cells that play a vital role in inflammation, immunity, and cancer. The spleen is an important source of monocytes, which act as direct precursors of haematopoietic stem cell–derived macrophages. Proteins related to the physiological processes involved in the immune system and cancer were significantly altered in TPC1 knockout (KO), TPC2 KO, and TPC1/2 double KO mouse splenocytes, compared to WT controls, suggesting that TPCs may play significant roles in regulating innate immune system functions in various pathophysiological processes. My thesis studies have identified TPC2 as a major regulator of monocyte differentiation and macrophage development. In addition, my studies have revealed, for the first time, an important link between TPC2 and the release of two mediators that are opposed in their functions: IL-8 pro-inflammatory cytokine and IL-10 anti-inflammatory cytokine. Finally, I have discovered variants in the TPCN2 gene that are associated with cancer at the global level or 13 various cancer types at the local level, in the definition of tumour types, susceptibility, and prognosis in the UK-biobank. My thesis gives insights into the pathophysiological significance of TPC2 in cancer immunity and may contribute to the development of new genomics-based guidelines for cancer diagnosis and therapy. |
| spellingShingle | Alharbi, A Deciphering the role of endolysosomal Ca2+ signalling via two-pore channel 2 (TPC2) in cancer: from bench to bedside |
| title | Deciphering the role of endolysosomal Ca2+ signalling via two-pore channel 2 (TPC2) in cancer: from bench to bedside
|
| title_full | Deciphering the role of endolysosomal Ca2+ signalling via two-pore channel 2 (TPC2) in cancer: from bench to bedside
|
| title_fullStr | Deciphering the role of endolysosomal Ca2+ signalling via two-pore channel 2 (TPC2) in cancer: from bench to bedside
|
| title_full_unstemmed | Deciphering the role of endolysosomal Ca2+ signalling via two-pore channel 2 (TPC2) in cancer: from bench to bedside
|
| title_short | Deciphering the role of endolysosomal Ca2+ signalling via two-pore channel 2 (TPC2) in cancer: from bench to bedside
|
| title_sort | deciphering the role of endolysosomal ca2 signalling via two pore channel 2 tpc2 in cancer from bench to bedside |
| work_keys_str_mv | AT alharbia decipheringtheroleofendolysosomalca2signallingviatwoporechannel2tpc2incancerfrombenchtobedside |