Nat Med | He huarahi maha-omics hei mahere i te pukupuku whakauru

Nat Med | Mā te huarahi maha-omics hei mahere i te whenua whakauru o te pukupuku, te ārai mate me te moroiti o te mate pukupuku koroni ka kitea te taunekeneke o te moroiti me te pūnaha ārai mate.
Ahakoa kua rangahaua whānuitia ngā tohu koiora mō te mate pukupuku koroni tuatahi i ngā tau tata nei, ko ngā aratohu haumanu o nāianei e whakawhirinaki ana ki te whakatau i te horapa o te pūtau pukupuku-lymph me te kimi i ngā hapa whakatikatika DNA (MMR) me te kore pumau o te microsatellite (MSI) (hei tāpiri atu ki ngā whakamātautau pathology paerewa) hei whakatau i ngā taunakitanga maimoatanga. Kua kitea e ngā kairangahau te kore hononga i waenga i ngā urupare ārai mate e ahu mai ana i te whakaaturanga ira, ngā kōtaha moroiti, me te stroma pukupuku i roto i te rōpū mate pukupuku colorectal Cancer Genome Atlas (TCGA) me te oranga o te tūroro.

I te whanaketanga o ngā rangahau, kua pūrongohia he hononga nui ngā āhuatanga tauanga o te mate pukupuku colorectal tuatahi, tae atu ki te āhua pūtau, te āhua ārai mate, te āhua stromal, te āhua moroiti rānei o te mate pukupuku, ki ngā putanga haumanu, engari he iti tonu te māramatanga mō te pānga o ēnei taunekeneke ki ngā putanga o te tūroro.
Hei wetewete i te whanaungatanga i waenga i te uaua o te āhua me te putanga, i whakawhanakehia, i whakamanahia hoki e tētahi rōpū kairangahau mai i te Sidra Institute of Medical Research i Qatar tētahi kaute whakauru (mICRoScore) e tautuhi ana i tētahi rōpū tūroro he pai ngā reiti oranga mā te whakakotahi i ngā āhuatanga microbiome me ngā pūmau whakakorenga ārai mate (ICR). I whakahaerehia e te rōpū he tātaritanga ira whānui o ngā tauira tio hou mai i te 348 tūroro me te mate pukupuku colorectal tuatahi, tae atu ki te raupapatanga RNA o ngā pukupuku me te kiko colorectal hauora kua ōrite, te raupapatanga exome katoa, te kaiwhakawhiwhi pūtau-T hohonu me te raupapatanga ira rRNA huakita 16S, me te tāpiritanga o te raupapatanga ira pukupuku katoa hei whakaahua ake i te microbiome. I whakaputaina te rangahau i roto i te Nature Medicine hei "He atlas whakauru o te pukupuku, te ārai mate me te microbiome o te mate pukupuku koroni".

He tuhinga i whakaputaina ki te Nature Medicine

Tirohanga Whānui mō te AC-ICAM

I whakamahia e ngā kairangahau tētahi tūāpapa ira-ā-ira orthogonal hei tātari i ngā tauira pukupuku hou kua tio, ā, i taurite hoki ngā kiko koroni hauora e tata ana (ngā takirua pukupuku-noa) mai i ngā tūroro he mate pukupuku koroni kua tautuhia ki te histology, kāore he rongoā pūnaha. I runga i te raupapatanga exome-katoa (WES), te whakahaere kounga raraunga RNA-seq, me te tirotiro paearu whakauru, i puritia ngā raraunga ira-ā-ira mai i ngā tūroro 348, ā, i whakamahia mō te tātaritanga o muri mai me te aroturukitanga toharite o te 4.6 tau. I tapaina e te rōpū rangahau tēnei rauemi ko Sidra-LUMC AC-ICAM: He mahere me te aratohu ki ngā taunekeneke ārai mate-mate pukupuku-microbiome (Pikitia 1).

Te whakarōpūtanga ngota ngota mā te whakamahi i te ICR

Mā te hopu i tētahi huinga tohu ira ārai mate mō te tirotiro tonu i te mate pukupuku, e kiia nei ko te pūmau ārai mate o te whakakorenga (ICR), i arotau te tīma rangahau i te ICR mā te whakapoto hei rōpū ira-20 e kapi ana i ngā momo mate pukupuku rerekē, tae atu ki te melanoma, te mate pukupuku tōngāmimi, me te mate pukupuku ū. Kua honoa hoki te ICR ki te urupare ārai mate i roto i ngā momo mate pukupuku, tae atu ki te mate pukupuku ū.

Tuatahi, i whakamanahia e ngā kairangahau te waitohu ICR o te rōpū AC-ICAM, mā te whakamahi i tētahi huarahi whakarōpūtanga ira-ICR hei whakarōpū i te rōpū kia toru ngā rōpū/momo ārai mate: te ICR teitei (ngā pukupuku wera), te ICR waenga me te ICR iti (ngā pukupuku makariri) (Pikitia 1b). I whakaahuahia e ngā kairangahau te āhua o te ārai mate e pā ana ki ngā momo ngota ngota whakaae (CMS), he whakarōpūtanga o te mate pukupuku koroni e pā ana ki te transcriptome. Ko ngā kāwai CMS i whakaurua ko te CMS1/ārai mate, CMS2/canonical, CMS3/metabolic me te CMS4/mesenchymal. I whakaatuhia e te tātaritanga he hononga kino ngā kaute ICR ki ētahi ara pūtau mate pukupuku i roto i ngā momo CMS katoa, ā, ko ngā hononga pai ki ngā ara ārai mate me ngā ara e pā ana ki te stromal i kitea anake i roto i ngā pukupuku CMS4.

I roto i ngā CMS katoa, ko te nui o ngā pūtau kaikōhuru taiao (NK) me ngā pūtau-T i teitei rawa atu i roto i ngā momo ārai mate ICR teitei, me te rerekētanga nui ake i roto i ētahi atu momo leukocyte (Pikitia 1c). He rerekē te OS me te PFS o ngā momo ārai mate ICR, me te pikinga haere o te ICR mai i te iti ki te teitei (Pikitia 1d), e whakamana ana i te tūranga matapae o te ICR i roto i te mate pukupuku colorectal.

Pikitia 1. Te hoahoa rangahau AC-ICAM, te waitohu ira e pā ana ki te ārai mate, ngā momo ira ārai mate me ngā momo ngota ngota me te oranga tonutanga.
Ka hopukina e te ICR ngā pūtau-T kua whakanuia ki te pukupuku, kua whakanuia hoki e te clonal
He iti noa iho ngā pūtau-T e uru ana ki te kiko pukupuku kua pūrongohia he motuhake mō ngā antigens pukupuku (iti iho i te 10%). Nō reira, ko te nuinga o ngā pūtau-T o roto i te pukupuku e kiia ana ko ngā pūtau-T tū tata (ngā pūtau-T tū tata). Ko te hononga kaha rawa atu ki te maha o ngā pūtau-T tikanga me ngā TCR hua i kitea i roto i ngā taupori pūtau stromal me ngā taupori leukocyte (i kitea e te RNA-seq), ka taea te whakamahi hei whakatau tata i ngā taupori pūtau-T (Pikitia 2a). I roto i ngā tautau ICR (te whakarōpūtanga whānui me te CMS), ko te clonality teitei rawa o ngā TCR SEQ ārai mate i kitea i roto i ngā rōpū ICR-tiketike me te momo CMS CMS1/ārai mate (Pikitia 2c), me te ōwehenga teitei rawa o ngā pukupuku ICR-tiketike. Mā te whakamahi i te transcriptome katoa (18,270 ira), e ono ngā ira ICR (IFNG, STAT1, IRF1, CCL5, GZMA, me CXCL10) i roto i ngā ira tekau o runga e hono pai ana ki te clonality SEQ ārai mate TCR (Pikitia 2d). He kaha ake te hononga o te hononga ā-ira TCR o ImmunoSEQ ki te nuinga o ngā ira ICR i ngā hononga i kitea mā te whakamahi i ngā tohu CD8+ e aro ana ki te pukupuku (Pikitia 2f me 2g). Hei whakamutunga, e kī ana te tātaritanga i runga ake nei ka hopukina e te waitohu ICR te aroaro o ngā pūtau-T kua whakanuia ki te pukupuku, kua whakanuia ki te koroni, ā, tera pea ka whakamārama i ōna pānga matapae.

Pikitia 2. Ngā inenga TCR me te hononga ki ngā ira e pā ana ki te ārai mate, ngā momo ira me ngā momo ngota ngota.
Te hanganga o te microbiome i roto i ngā kiko hauora me ngā kiko matepukupuku koroni
I whakahaerehia e ngā kairangahau te raupapatanga 16S rRNA mā te whakamahi i te DNA i tangohia mai i te pukupuku taurite me te kiko koroni hauora mai i te 246 tūroro (Pikitia 3a). Hei whakamana, i tātarihia anō e ngā kairangahau ngā raraunga raupapatanga ira 16S rRNA mai i ētahi atu tauira pukupuku 42 kāore i rite te DNA noa e wātea ana mō te tātari. Tuatahi, i whakaritea e ngā kairangahau te nui o ngā tipu i waenga i ngā pukupuku taurite me te kiko koroni hauora. I tino piki ake te Clostridium perfringens i roto i ngā pukupuku ki te whakataurite ki ngā tauira hauora (Pikitia 3a-3d). Kāore he rerekētanga nui i roto i te kanorau alpha (te kanorau me te nui o ngā momo i roto i te tauira kotahi) i waenga i ngā tauira pukupuku me ngā tauira hauora, ā, i kitea he whakahekenga iti i roto i te kanorau moroiti i roto i ngā pukupuku ICR-tiketike e whakataurite ana ki ngā pukupuku ICR-iti.
Hei kimi i ngā hononga e pā ana ki te haumanu i waenga i ngā kōtaha moroiti me ngā putanga haumanu, i whai ngā kairangahau ki te whakamahi i ngā raraunga raupapatanga ira 16S rRNA hei tautuhi i ngā āhuatanga moroiti e tohu ana i te oranga. I te AC-ICAM246, i whakahaerehia e ngā kairangahau he tauira whakatauira OS Cox i tīpakohia ai ngā āhuatanga 41 me ngā tauwehenga kore-kore (e pā ana ki te mōrearea mate rerekē), e kiia nei ko ngā whakarōpūtanga MBR (Pikitia 3f).
I roto i tēnei rōpū whakangungu (ICAM246), i honoa te kaute MBR iti (MBR<0, MBR iti) ki te iti rawa o te mōrearea o te mate (85%). I whakaūhia e ngā kairangahau te hononga i waenga i te MBR iti (mōrearea) me te OS roa i roto i ngā rōpū e rua kua whakamanahia motuhake (ICAM42 me TCGA-COAD). (Pikitia 3) I whakaatuhia e te rangahau he hononga kaha i waenga i te cocci endogastric me ngā kaute MBR, he rite tonu i roto i te pukupuku me te kiko koroni hauora.

Pikitia 3. Te koiora i roto i te pukupuku me ngā kiko hauora me te whanaungatanga ki te ICR me te oranga o te tūroro.
Whakamutunga
Mā te huarahi maha-omics i whakamahia i roto i tēnei rangahau ka taea te kimi me te tātari hōhonu i te waitohu ngota o te urupare ārai mate i roto i te mate pukupuku colorectal, ā, ka whakakitea te taunekeneke i waenga i te microbiome me te pūnaha ārai mate. I whakaatuhia e te raupapatanga TCR hohonu o te pukupuku me ngā kiko hauora ko te pānga matapae o te ICR pea nā tōna kaha ki te hopu i ngā tārua pūtau-T kua whakanuia ki te pukupuku, me te pea he antigen pukupuku-motuhake.

Mā te tātari i te hanganga o te microbiome pukupuku mā te whakamahi i te raupapatanga ira 16S rRNA i roto i ngā tauira AC-ICAM, i kitea e te tīma he waitohu microbiome (kaute mōrearea MBR) me te uara matapae kaha. Ahakoa i ahu mai tēnei waitohu i ngā tauira pukupuku, he hononga kaha i waenga i te colorectum hauora me te kaute mōrearea MBR pukupuku, e kī ana ka hopukina pea e tēnei waitohu te hanganga microbiome puku o ngā tūroro. Mā te whakakotahi i ngā kaute ICR me MBR, i taea te tautuhi me te whakamana i tētahi tohu koiora ākonga maha-omic e tohu ana i te oranga o ngā tūroro e pangia ana e te mate pukupuku koroni. Ko te huinga raraunga maha-omic o te rangahau e whakarato ana i tētahi rauemi hei mārama ake i te koiora mate pukupuku koroni me te āwhina ki te kimi i ngā huarahi rongoā whaiaro.

Tohutoro:
Roelands, J., Kuppen, PJK, Ahmed, EI et al. He puku whakauru, mate pukupuku me te microbiome atlas o te mate pukupuku koroni. Nat Med 29, 1273–1286 (2023).